Recently, sodium-glucose co-transport (SGLT) inhibitors have been found to be effective in treating prediabetes, type 1 or type 2 diabetes mellitus. Particularly SGLT2 inhibitors have been shown to block the reabsorption of glucose from the renal filtrate in the glomerulus thereby inducing glucose excretion in the urine. As excess glucose is excreted, there is a decrease in blood glucose level, decreased hepatic storage of glucose, decreased insulin secretion and, subsequently, decreased carbohydrate conversion to fat and, ultimately, reduced accumulated fat. Selective inhibition of SGLT2 is expected to normalize plasma glucose by enhancing glucose excretion. Consequently, SGLT2 inhibitors provide an attractive means for the improvement of diabetic conditions without increasing body weight or the risk of hypoglycemia. See, Isaji, M., Current Opinion Investigational Drugs, 8(4), 285-292 (2007). For a general review of SGLT as a therapeutic target, see also Asano, T., et al., Drugs of the Future, 29(5), 461-466 (2004).
Nephropathy is a well-established complication of poor glycemic control in patients with diabetes. An estimated 10-36% of patients with type 2 diabetes mellitus (T2DM) have some degree of renal impairment and chronic kidney disease (CKD) is present in approximately 40% of patients with diabetes. CKD has been classified into 5 stages, where stage 1 is kidney damage with normal GFR (mL/min/1.73 m2) of 90; stage 2 is kidney damage with a mild decrease in glomerular filtration rate (GFR) (GFR 60-89); stage 3 is a moderate decrease in GFR (GFR 30-59); stage 4 is a severe decrease in GFR (GFR 15-29); and stage 5 is kidney failure (GFR<15 or dialysis). The use of a number of anti-diabetes agents is restricted in patients with renal impairment. Therefore, there is a need for methods, medicaments and pharmaceutical compositions for the treatment of metabolic disorders, such as type 2 diabetes, in patients with renal impairment or chronic kidney disease (CDK).
Additionally, SGLT plays a role at the blood brain barrier in the blood-to-brain transport of glucose during ischemic conditions, and inhibition of SGLT during stroke has the potential to improve stroke outcomes (Vemula et al., A Functional Role for Sodium-Dependent Glucose Transport across the Blood-Brain Barrier during Oxygen Glucose Deprivation, The Journal of Pharmacology and Experimental Therapeutics, Vol. 328:487-495, 2009). Studies have also shown that post-ischemic hyperglycemia exacerbates the development of cerebral ischemic neuronal damage through the cerebral sodium-glucose transporter, and that neuronal damage following hyperglycemia was not observed following administration of phlorizin, an SGLT1 and SGLT2 inhibitor (Yamazaki et al., Post-ischemic hyperglycemia exacerbates the development of cerebral ischemic neuronal damage through the cerebral sodium-glucose transporter, Brain Research 1489:113-120, 2012). Thus, SGLT-2 inhibitors could be useful for reducing neuronal damage following the incidence of ischemic stroke and close-head traumatic brain injury. Therefore, there is a need for methods, medicaments and pharmaceutical compositions for use in the reduction of neuronal damage following the incidence of ischemic stroke and close-head traumatic brain injury.